The chromosome bands 15q24.1-15q24.3 contain a complex region
with numerous segmental duplications that predispose to regional
microduplications and microdeletions, both of which have been
linked to intellectual disability, speech delay and autistic
features. The region may also harbour common inversion
polymorphisms whose functional and phenotypic manifestations are
unknown. Using single nucleotide polymorphism (SNP) data, we
detected four large contiguous haplotype-genotypes at 15q24 with
Mendelian inheritance in 2,562 trios, African origin, high
population stratification and reduced recombination rates.
Although the haplotype-genotypes have been most likely generated
by decreased or absent recombination among them, we could not
confirm that they were the product of inversion polymorphisms in
the region. One of the blocks was composed of three
haplotype-genotypes (N1a, N1b and N2), which significantly
correlated with intelligence quotient (IQ) in 2,735 children of
European ancestry from three independent population cohorts.
Homozygosity for N2 was associated with lower verbal IQ
(2.4-point loss, p-value = 0.01), while homozygosity for N1b was
associated with 3.2-point loss in non-verbal IQ (p-value =
0.0006). The three alleles strongly correlated with expression
levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for
N2 correlated with over-expression of MAN2C1 over many brain
areas but the occipital cortex where N1b homozygous highly
under-expressed. Our population-based analyses suggest that
MAN2C1 may contribute to the verbal difficulties observed in
microduplications and to the intellectual disability of
microdeletion syndromes, whose characteristic dosage increment
and removal may affect different brain areas.